The present invention relates to substituted sulfonamide compounds, processes for their preparation, medicaments containing these compounds, and the use of substituted sulfonamide compounds for the preparation of pharmaceutical compositions.
In contrast to the constitutive expression of the bradykinin 2 receptor (B2R) the bradykinin 1 receptor (B1R) is not expressed, or is only weakly expressed in most tissues. However, the expression of B1R can be induced in various cells. For example, in the course of inflammatory reactions there is a rapid and pronounced induction of B1R on neuronal cells but also on various peripheral cells such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. In the course of inflammatory reactions there is thus a switch from a B2R to a B1R dominance on the involved cells. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) (Passos et al. J. Immunol. 2004, 172, 1839-1847) are significantly involved in this up-regulation. After activation with specific ligands, B1R-expressing cells can then themselves secrete inflammation-promoting cytokines such as IL-6 and IL-8 (Hayashi et al. Eur. Respir. J. 2000, 16, 452-458). This leads to the inflow of further inflammatory cells, e.g. neutrophilic granulocytes (Pesquero et al. PNAS 2000, 97, 8140-8145). Via these mechanisms the bradykinin B1R system can contribute to the chronic condition of diseases. This is confirmed by a number of animal experiment investigations (reviews in Leeb-Lundberg et al., Pharmacol Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem., 2006, 387, 119-126). An enhanced expression of B1R is also found in humans, for example on enterocytes and macrophages in the affected tissue of patients suffering from inflammatory intestinal diseases (Stadnicki et al. Am. J. Physio. Gastrointest. Liver Physiol. 2005, 289, G361-366) and on T lymphocytes of patients suffering from multiple sclerosis (Pratet et al., Neurology, 1999, 53, 2087-2092) or an activation of the bradykinin B2R-B1R system during infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for clinical conditions ranging from surface infections of the skin up to septic shock.
Due to the pathophysiological relationships outlined above, there is a great therapeutic potential for the use of B1R antagonists in acute and in particular chronic-inflammatory diseases. These include diseases of the respiratory tract (bronchial asthma, allergies, COPD (chronic obstructive pulmonary disease), cystic fibrosis, etc.), inflammatory intestinal diseases (ulcerative colitis, CD (Crohn's disease), etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections, etc.) and mucous membranes (M. Behcet, pelvitis, prostatitis), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock, and reperfusion syndrome (after heart attacks and strokes).
In addition the bradykinin (receptor) system is also involved in the regulation of angiogenesis (potential as an angiogenesis inhibitor in cancer and also macular degeneration of the eye) and B1R knockout mice are protected against the danger of becoming overweight due to a particularly fat-rich diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore also suitable for treating obesity.
B1R antagonists are in particular suitable for treating pain, in particular inflammatory pain and neuropathic pain (Calixto et al. Br. J. Pharmacol 2004, 1-16), in this connection in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). Furthermore they are suitable for the treatment of migraine.
In the development of B1R modulators there is the problem however that the human and rat B1R receptors differ so greatly that many compounds that are good B1R modulators on the human receptor have only a poor affinity or no affinity at all for the rat receptor. This significantly complicates animal pharmacological investigations since many investigations are normally carried out on rats. If however a compound has no effect on the rat receptor, then neither the action nor side effects on rats can be investigated. This has already led to the creation of transgenic animals with human B1 receptors for animal pharmacological investigations (Hess et al., Biol. Chem. 2006; 387(2): 195-201). Working with transgenic animals is however more costly than working with unaltered animals. Since long-term toxicity investigations on rats are in particular part of the routine investigations in drug research and development however, these are not practicable if the compound is ineffective on the receptor, and an important established tool for checking safety is therefore lacking in the development of such compounds. There is therefore a need for new B1R modulators, in which connection B1R modulators that bind to the rat receptor as well as to the human receptor offer particular advantages.